Regression with frailty in survival analysis

In studies of survival, the hazard function for each individual may depend on observed risk variables but usually not all such variables are known or measurable. This unknown factor of the hazard function is usually termed the individual heterogeneity or frailty. When survival is time to the occurrence of a particular type of event and more than one such time may be obtained for each individual, frailty is a common factor among such recurrence times. A model including frailty is fitted to such repeated measures of recurrence times.     

Phytoremediation of Organic Contaminants: A Review of Phytoremediation Research at the University of Washington

As overwhelmingly positive results have become available regarding the ability of plants to degrade compounds such as trichloroethylene, phytoremediation studies are expanding. Studies to determine the potential for phytoremediation of fully chlorinated compounds, such as carbon tetrachloride and tetrachloroethylene, brominated compounds, such as ethylene dibromide and dibromochloropropane, and nonhalogenated compounds, such as methyl-t-butyl ether (MTBE), are underway. When using phytoremediation, it is important to select not only a plant that is capable of degrading the pollutant in question, but also one that will grow well in that specific environment. In ecologically sensitive areas, such as the Hawaiian Islands, only plants native to the area can be used. One way to supplement the arsenal of plants available for remedial actions is to utilize genetic engineering tools to insert into plants those genes that will enable the plant to metabolize a particular pollutant. Hybrid technologies, such as using plants in pumping and irrigation systems, also enable plants to be used as a remedial method when the source of the pollutant is beyond the reach of plant roots, or when planting space directly over the pollutant is unavailable or restricted. Thus, the potential uses of phytoremediation are expanding as the technology continues to offer new, low-cost remediation options.     

Profiling for novel proteomics biomarkers in neurodevelopmental disorders

Protein biomarker discovery from biological fluids, such as serum, has been widely applied to disorders such as cancer and has more recently also been utilized in neuro-psychiatric disorders with relatively clear biological causes, such as Alzheimer's disease and schizophrenia. The application of the associated technologies for the identification of protein biomarker signatures in neurodevelopmental disorders, such as autism spectrum disorder and attention deficit hyperactivity disorder, is comparatively less well established. The aim of this article is to provide an overview of the various protocols available for such analysis, discuss reports in which these techniques have been previously applied in biomarker discovery/validation in neurodevelopmental disorders, and consider the future development of this area of research.     

Brief communication: Choice of washing method of hair samples for trace element analysis in environmental studies.

Determination of inseparable exogenous and endogenous levels of toxic trace elements such as lead in human scalp hair has been used to understand and assess population exposure to such elements. For any such analysis, washing of the hair samples to remove superficial contamination is the foremost requirement. However, the use of such washing methods prior to elemental analysis removes minute quantities of trace elements from the hair strands. This degree of loss is dependent on the washing method employed. In the present study, the element lead has been determined in human scalp hair after three methods of hair washing. It is apparent that the nonionic detergent-acetone method is best suited for securing valid lead analysis results in human scalp hair.     

On the rotational brownian motion of a bacterial idle motor. I. Theory of time-dependent fluorescence depolarization

A rotational diffusion equation and its Green's function for a spheroidal particle such as a bacterial body, to which an actively driving but idle motor is attached, are presented. As an application of the theory, general expressions for the time-dependent fluorescence depolarization caused by such a particle have been obtained. Measurement of such depolarizalion should provide a useful tool for determination of the rate of revolution of the rotating motor attached to cell bodies such as bacteria under various solution conditions, if a fluorescent (or phosphorescent) label is attached to the motor shaft.     

The ever-changing brain: cellular and molecular mechanisms for the effects of stressful experiences

The adult brain is capable of considerable structural and functional plasticity and the study of hormone actions in brain has contributed to our understanding of this important phenomenon. In particular, stress and stress-related hormones such as glucocorticoids and mineralocorticoids play a key role in the ability of acute and chronic stress to cause reversible remodeling of neuronal connections in the hippocampus, prefrontal cortex, and amygdala. To produce this plasticity, these hormones act by both genomic and non-genomic mechanisms together with ongoing, experience-driven neural activity mediated by excitatory amino acid neurotransmitters, neurotrophic factors such as brain derived neurotrophic factor, extracellular molecules such as neural cell adhesion molecule, neuropeptides such as corticotrophin releasing factor, and endocannabinoids. The result is a dynamic brain architecture that can be modified by experience. Under this view, the role of pharmaceutical agents, such as antidepressants, is to facilitate such plasticity that must also be guided by experiences.     

The Behavior of the Hydrophobic Effect under Pressure and Protein Denaturation

It is well known that proteins denature under high pressure. The mechanism that underlies such a process is still not clearly understood, however, giving way to controversial interpretations. Using molecular dynamics simulation on systems that may be regarded experimentally as limiting examples of the effect of high pressure on globular proteins, such as lysozyme and apomyoglobin, we have effectively reproduced such similarities and differences in behavior as are interpreted from experiment. From the analysis of such data, we explain the experimental evidence at hand through the effect of pressure on the change of water structure, and hence the weakening of the hydrophobic effect that is known to be the main driving force in protein folding.     

The Nernst equation applied to oxidation-reduction reactions in myoglobin and hemoglobin. Evaluation of the parameters

Analyses of the binding of oxygen to monomers such as myoglobin employ the Mass Action equation. The Mass Action equation, as such, is not directly applicable for the analysis of the binding of oxygen to oligomers such as hemoglobin. When the binding of oxygen to hemoglobin is analyzed, models incorporating extensions of mass action are employed. Oxidation-reduction reactions of the heme group in myoglobin and hemoglobin involve the binding and dissociation of electrons. This reaction is described with the Nernst equation. The Nernst equation is applicable only to a monomeric species even if the number of electrons involved is greater than unity. To analyze the oxidation-reduction reaction in a molecule such as hemoglobin a model is required which incorporates extensions of the Nernst equation. This communication develops models employing the Nernst equation for oxidation-reduction reactions analogous to those employed for hemoglobin in the analysis of the oxygenation (binding of oxygen) reaction.     

Selling organs and souls: Should the state prohibit ‘demeaning’ practices?

It is sometimes argued that practices such as organ-selling should be prohibited because they are demeaning to the individuals involved. In this article the plausibility of such an argument is questioned. I will examine what it means to demean or be demeaned, and suggest that the mere fact that an individual is demeaning themself does not provide sufficient justification for legal prohibition. On the contrary, such laws might be argued to be demeaning.     

The reliability of relative anion-cation permeabilities deduced from reversal (Dilution) potential measurements in ion channel studies

Measurements of anion-cation permeability ratios (e.g., P _Cl/P _Na) are most readily made by measuring changes in zero-current reversal potential when the salt concentration on one side of the membrane (e.g., external NaCl) is decreased. This is particularly useful for measuring changes in ion selectivity in wild-type and mutant channels, such as those of the ligand-gated ion channel superfamily, and has shown that many of these channels have a significant permeability to counter-ions. One Brownian dynamics study of ion permeation through such narrow ion channels failed to observe such counter-ion movement, although later, another Brownian dynamics study did observe counter-ion movement through simulations of the same channels. The question has been raised as to the reliability of such reversal potential measurements for determining permeability ratios, particularly given the use of an equation such as the Goldman-Hodgkin-Katz (GHK) equation, which is often used to calculate such ratios. A new derivation of the GHK equation in terms of activity coefficients is also included. The application of irreversible thermodynamics will be shown to qualitatively support the reliability of such experimental anion-cation permeability values derived from reversal potential measurements. It will then be shown that for such zero-current situations, different electrodiffusion models, with very different underlying assumptions, produce almost identical relative permeabilities (and reversal potentials). Finally, the results of the two Brownian dynamics simulation studies and the relationship between reversal potentials and relative permeability will be discussed.     

Prospect for feedback guided surgery with ultra-short pulsed laser light

The controlled cutting of tissue with laser light is a natural technology to combine with automated stereotaxic surgery. A central challenge is to cut hard tissue, such as bone, without inducing damage to juxtaposed soft tissue, such as nerve and dura. We review past work that demonstrates the feasibility of such control through the use of ultrafast laser light to both cut and generate optical feedback signals via second harmonic generation and laser induced plasma spectra.     

Image plate detectors for macromolecular neutron diffractometry

Neutron diffraction studies of macromolecules require large position sensitive detectors. It is proposed that such a device can be based on image plate technology, which relies on re-usable photostimuable phosphors, combined with a neutron to gamma-ray converter. Design parameters such as the best wavelength for the neutron radiation and the optimum sample to detector distance are discussed, and a design for a cylindrical detector is outlined. Presently a prototype of such a detector is being built, and the very first test-recording of an X-ray diffraction pattern from a protein crystal is presented.     

Functional significances of the cytoskeleton

Functional significances of the cytoskeleton and the plasmalemmal undercoat are discussed with special reference to their ultrastructural aspects. The cytoskeleton is mainly composed of three distinctive cytoplasmic fibrous structures, namely, microtubules, actin filaments and intermediate filaments. Closely associated with such fibrous structures are a variety of proteins, which have been shown not only to control the formation or breakdown of the fibrous structures but also to involve the construction of a higher order of fibrous architectures such as bundles and networks. Thus, these cytoskeletal fibrous components may form the respective systems, though such systems often interact with each other for the cytoplasmic integrity. The fundamental function of the cytoskeleton is to provide structural frameworks for the cytoplasm. Through such frameworks the cytoskeleton is involved in various cellular organizations and activities such as cell shape, distribution of cell organelles, cell motility, membrane phenomena, and metabolism. Much interest has also been drawn to the interaction between the plasmalemma and the cytoskeleton. Part of such interaction can be assigned to the plasmalemmal undercoat, though it indeed constitutes a part of the cytoskeleton. The significance of the plasmalemmal undercoat may be to primarily provide structural supports for the plasmalemma, playing various roles in cell physiology.     

Research samples from families with genetic diseases: a proposed code of conduct.

Research on samples from families with genetic disease underlies many of the major advances that are occurring in medical genetics. But ethical and practical problems may arise when samples from relatives who are healthy but at risk are included in such studies. In particular, new molecular tests for specific gene mutations may result in the detection of a genetic defect in relatives who had neither expected this possibility nor given specific consent to such testing. Family members at risk should not be included in such studies unless strictly necessary, and in such cases specific consent should be obtained and information should be given about the implications of an abnormal result of a test. This is particularly important when stored samples from previous studies without such implications are being reused and is also relevant to the genetic testing of samples taken primarily for epidemiological studies of disorders when only a small proportion of cases is thought to be genetic in origin. There is a need for guidelines to protect both subjects and investigators in a field which is spreading rapidly and involving many clinical and laboratory research workers previously unfamiliar with genetic testing.     

Spatial Ultimatum Games, collaborations and the evolution of fairness

It is often the case that individuals in a social group can perform certain tasks (such as hunting, for example) more efficiently if they collaborate with other individuals than if they act alone. In such situations one is necessarily faced with the problem of how the resource obtained as the result of such a collaboration should be divided among the collaborating individuals. If one of the individuals in the collaboration is in a position (through its dominance rank, for example) to impose a particular division of the resource on the other members of the collaboration then we show that an evolutionary dilemma arises which prevents such collaborations being evolutionarily stable. This dilemma, which is closely related to the well-known Ultimatum Game, results from the fact that in such situations natural selection favours individuals who, if dominant, offer smaller and smaller shares of the resource to the others and, if subdominant, will accept lower and lower offers. We also show, however, that this dilemma is naturally resolved in a spatially structured population with selection favouring the evolution of a fair division of the resource and consequently ensuring the evolutionary stability of collaborations of this type.     

Factors Affecting the Respiration of Intertidal Invertebrates

The nature and rate of gas exchange in intertidal organismsis variable and is the product of an extremely complex environmentalsituation. Such influences may be grouped into tidal-dependentfactors such as the proportion of time spent exposed to air,the magnitude of environmental temperature fluctuations, andthe availability of food. Factors which may be regarded as generallyoperating independently of tidal level include latitudinal variationsin environmental temperature. Superimposed upon such spatialenvironmental variations are seasonal factors such as temperatureand photoperiod, which impose a temporal cycle upon the metabolicrate. Finally, there are numerous endogenous factors such asbody size, activity level, and stage of development which profoundlyinfluence the rate of respiration. It can be shown that somefactors, such as aerial or aquatic conditions, may affect respirationqualitatively. Under aquatic conditions gas exchange is withthe surrounding sea water, but with increasing exposure to airintertidal invertebrates are able to respire aerially and towithstand the water loss associated with this process. Manyare also able to respire anaerobically under conditions of stress.In contrast, factors such as activity level, body size, nutritionalconditions, and exposure temperature affect respiration quantitativelyand are often interdependent. The metabolism of intertidal animalsis then endowed with considerable flexibility between the extremesset by the active and standard rates of respiration. This activerate of respiration is markedly temperature-dependent in mostinstances, whereas the standard rate, which is characteristicof quiescent animals, is not only lower but often has a lowtemperature coefficient. A reduction in respiration conservesmetabolic reserves during periods of stress, and the low temperaturecoefficient further minimizes depletion of such reserves despitethe high environmental temperatures which often prevail duringthe intertidal period.     

Detecting interaction between random region and fixed age effects in disease mapping

The purpose of this article is to draw attention to the possible need for inclusion of interaction effects between regions and age groups in mapping studies. We propose a simple model for including such an interaction in order to develop a test for its significance. The assumption of an absence of such interaction effects is a helpful simplifying one. The measure of relative risk related to a particular region becomes easily and neatly summarized. Indeed, such a test seems warranted because it is anticipated that the simple model, which ignores such interaction, as is in common use, may at times be adequate. The test proposed is a score test and hence only requires fitting the simpler model. We illustrate our approaches using mortality data from British Columbia, Canada, over the 5-year period 1985-1989. For this data, the interaction effect between age groups and regions is quite large and significant.     

Cell contact-mediated signaling of monocytes by stimulated T cells: a major pathway for cytokine induction

T lymphocytes are currently thought to play a pivotal part in the pathogenesis of chronic inflammatory diseases. However, the mechanism(s) by which they exert their pathogenic effect remain(s) elusive. Contact-mediated signaling of monocytes by stimulated T cells is a potent pro-inflammatory mechanism that triggers massive up-regulation of the pro-inflammatory cytokines interleukin-1 (IL-1) and tumor necrosis factor-a (TNF-alpha) that play an important part in chronic destructive diseases such as rheumatoid arthritis and multiple sclerosis. To date cell-cell contact is the only endogenous mechanism to be described that displays such an activity in monocyte-macrophages which are classically stimulated in vitro by bacterial products such as LPS or non-specific stimuli such as phorbol esters or poorly activated by soluble cytokines such as IFN-gamma. Since direct cellular contact occurs at the inflammatory site, we hypothesized that this mechanism is relevant to the pathogenesis of chronic inflammatory disorders. This review aims at summarizing the state of the art and importance of contact-mediated monocyte activation by stimulated T lymphocytes.